Antiarrhythmic agents

ABSTRACT

Novel 1-aryl-1-benzocycloalkyl-4-aminobutanes and 1-aryl-1-benzocycloalkyl-4-amino-1-butenes are useful as antiarrhythmic agents.

This is a division of application Ser. No. 485,488, filed July 3, 1974.

BACKGROUND OF THE INVENTION

This invention relates to certain butylamines and butenylamines. Inparticular, this invention relates to certain butyl and butenylamineshaving aryl and benzocycloalkyl disubstitution in the 4-position. Thenovel compounds provided herein are valuable pharmacological agents,especially useful in the treatment of cardiac arrhythmias in humans.

There are several types of arrhythmias which afflict mankind, and eachtype may have a different underlying condition as its cause. The moreserious conditions causing arrhythmias are generally myocardialinfarction and digitalis toxicity. When treating arrhythmias, it isimportant to understand the pharmacologic action of the drug being used,and it is important to remember that the pharmacologic action of thedrug selected may vary, depending on the state of the myocardium.Several drugs are available for treating cardiac arrhythmias. Quinidineis a drug that depresses myocardial contractility and decreases the rateof conduction in the myocardium. It is used mainly to preventtachyarrhythmias; however, several undesirable side effects normallyaccompany its use. Procainamide has practically the same pharmacologicalactions as quinidine, with about the same effect on arrhythmias; howeverprocainamide is safer than quinidine for intravenous use. Lidocaine isconsidered one of the most effective antiarrhythmic agents and is usedprimarily to combat ventricular tachyarrhythmias. It is especiallyuseful in patients with recent myocardial infarction. Lidocaine doesn'tcause a drop in blood pressure as does quinidine and procainamide;however, lidocaine does display toxic effects on the central nervoussystem, evidenced by symptoms such as drowsiness, twitchings andconvulsions.

Research scientists are constantly looking for new antiarrhythmic agentsbecause of the severity of these diseases of the heart, and because ofthe serious side effects commonly encountered with the use of currentlyavailable drugs. Several indanyl derivatives have recently been preparedwhich have displayed varying degrees of antiarrhythmic activity. Forexample, very potent antiarrhythmic agents, which areN,N-dialkyl-N'-(2-indanyl)-N'-phenyl alkylene diamines, are described inCanadian Pat. No. 910907.

The compounds of this invention are butylamine and butenylaminederivatives which display antiarrhythmic activity. It is an object ofthis invention to provide novel compounds which are useful in treatingcardiac arrhythmias.

SUMMARY OF THE INVENTION

The compounds of this invention have the formula ##STR1## in which m is0, 1, or 2; n is 0, 1, or 2, m + n is 2 or 3; R₁ and R₂ independentlyare hydrogen, C₁ -C₄ alkyl, or a lower alkenyl group having the formulaCH₂ R₄, in which R₄ is C₂ -C₅ alkenyl, or R₁ and R₂ together with theadjacent nitrogen atom form a heterocyclic ring system; R₃ is hydrogen,methyl, methoxy, trifluoromethyl, or halogen. X and Y are both hydrogen,or taken together X and Y form a double bond. The pharmaceuticallyacceptable acid addition salts are included within the scope of theinvention. Also included herein are the pharmaceutically acceptablequaternary ammonium salts of the tertiary amines of this invention.

The novel compounds provided by the present invention are prepared bytreating a readily available 1-aryl-1-benzocycloalkyl-1-butene, whichbutene bears in the 4-position a displaceable group such as a chlorineor bromine atom for instance, with an amine to provide the desired1-aryl-1-benzocycloalkyl-4-amino-1-butenes of the invention. Reductionof the butenes thus formed leads to the corresponding aminobutanes ofthe invention.

The compounds of this invention are useful in converting heartarrhythmias to a normal rhythm.

DETAILED DESCRIPTION OF THE INVENTION

As hereinbefore indicated, the compounds of this invention have theformula ##STR2##

R₁ and R₂ in the above formula are the same or are different and areselected from among hydrogen, C₁ -C₄ alkyl, or CH₂ R₄, wherein R₄ is C₂-C₅ alkenyl, or R₁ and R₂ together with the adjacent nitrogen atom forma ring system selected from among pyrrolidino, piperidone, ormorpholino.

Examples of C₁ -C₄ alkyl groups include both straight and branched chainlower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, and like groups.

R₁ and R₂ also can be alkenyl groups of the formula CH₂ R₄, examples ofwhich include 2-propenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl,3-methyl-3-pentenyl, 4-hexenyl, 5-hexenyl, and the like. R₃ in the aboveformula is a phenyl substituent selected from among hydrogen, methyl,methoxy, trifluoromethyl and halogen. The term "halogen" as used hereinrefers to fluorine, chlorine, bromine, and iodine. The preferredcompounds of the invention are those wherein R₃ is hydrogen.

X and Y are both hydrogen, or taken together, X and Y form a doublebond.

The aminobutenes and the aminobutanes of this invention aredisubstituted in the 4-position with a phenyl group and with abenzocycloalkyl group. As indicated in the above formula, thebenzocycloalkyl group can be an indanyl group or a tetrahydronaphthylgroup. For example, when m is 0 and n is 2, the substituent is a1-indanyl group, and when m is 1 and n is 1, the substituent is a2-indanyl group. Similarly, when m is 0 and n is 3, the substituent is a1-(1,2,3,4-tetrahydronaphthyl) group, and when m is 1 and n is 2, thesubstituent is a 2-(1,2,3,4-tetrahydronaphthyl group.

The pharmaceutically acceptable acid addition salts of the amines areincluded within the scope of this invention. Pharmaceutically acceptablesalts of amines are well known to those in the art, and it is generallyrecognized that the particular salt formed is not critical. The saltformed, however, must be pharmaceutically acceptable and substantiallynon-toxic to animal organisms. Typical acid addition salts are thoseprepared with the mineral acids, especially those prepared with acidssuch as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, andlike acids. Organic acids such as formic, acetic, butyric, citric,maleic, succinic, oxalic, benozic, methanesulfonic, p-toluenesulfonic,and the like, can also be used to form acceptable salts.

Pharmaceutically acceptable quaternary ammonium salts are also includedherein and are important pharmacological agents. The particular saltformed is not critical, but the salt must be substantially non-toxic toanimal organisms. Any of a number of anions can be associated withquaternary salts, and these are well known to chemists and biologists.Preferred quaternary ammonium salts are those prepared with C₁ -C₄ loweralkyl alkylating agents. Generally, these salts are prepared by treatingthe amine with alkylating agents such as alkyl halides, alkylsulfates,arylsulfonates, and the like. Typical alkylating agents include methyliodide, ethyl bromide, n-propyl chloride, dimethyl sulfate, isopropylbromide, isobutyl iodide, and the like. Other acceptable salts areprepared with CH₂ R₄ alkylating agents, wherein R₄ is as definedhereinabove. Examples of these alkylating agents include allyl bromide,3-butenyl iodide, 3-pentenyl chloride, 4-pentenyl chloride, 5-hexenyliodide, and the like. When the anion of a quaternary ammonium salt is ahalide ion, these anions can be replaced by other anions if desired, forexample by metathesis. An anion such as sulfate, sulfonate, nitrate,hydroxide, perchlorate, tetrafluoroborate, acetate, butyrate, and thelike, can be incorporated into the ammonium salt if desired.

Illustrative examples of compounds provided by the present invention areas follows:

1-Phenyl-1-(2-indanyl)-4-aminobutane;

1-Phenyl-1-(2-indanyl)-4-methylamino-1-butene;

1 -Phenyl-1-(2-indanyl)-4-isobutylaminobutane;

1-(4-Trifluoromethylphenyl)-1-(2-indany;l)-4-allylamino-1-butene;

1-(3-Chlorophenyl)-1-(2-indanyl)-4-amino-1-butene;

1-(2-Methylphenyl)-1-(2-indanyl)-4-methylaminobutane;

1-Phenyl-1-(2-indanyl)-4-amino-1-butene hydrobromide;

1-Phenyl-1-(2-indanyl)-4-aminobutane hydroacetate;

1-Phenyl-1-(1-indanyl)-4-n-propylaminobutane hydroiodide;

1-Phenyl-1-(2-indanyl)-4-n-butylamino-1-butene hydrogen nitrate;

1-Phenyl-1-(2-indanyl)-4-(5-hexenylamino)butane hydrogen maleate;

1-Phenyl-1-(2-indanyl)-4-diethylaminobutane;

1-Phenyl-1-(2-indanyl)-4-diisopropylaminobutane;

1-(3-chlorophenyl)-1-(1-indanyl)-4-dimethylamino-butane;

1-(4-methylphenyl)-1-(2-indanyl)-4di-n-propyl-l-butene;

1-Phenyl-1-(2-indanyl)-4-diethylamino-1-butene;

1-(3-methoxyphenyl)-1-(2-indanyl)-4-n-butylmethyl-amino-1-butene;

1-Phenyl-1-(2-indanyl)-4-piperidinobutane;

1-Phenyl-1-(2-indanyl)-4-morpholinobutane;

1-Phenyl-1-(2-indanyl)-4-pyrrolidinobutane;

1-(4-Trifluoromethylphenyl)-1-(2-indanyl)-4-diethylaminobutanehydrochloride;

[4-Phenyl-4-(2-indanyl)butyl]triethylammonium iodide;

[4-Phenyl-4-(2-indanyl)butyl]diethylmethylammonium methanesulfate;

[4-Phenyl-4-(1-indanyl)-3-butenyl]allyldiethylammonium bromide;

[4-Phenyl-4-(2-indanyl)-3-butenyl]trimethylammonium hydroxide.

1-Phenyl-1-[1-(1,2,3,4-tetrahydronaphthyl)]-4-di-isopropylaminobutane;

1-Phenyl-1-[2-(1,2,3,4-tetrahydronaphthyl)]-4-isopropylmethylaminobutane;

1-(2-Bromophenyl)-1-[-(1,2,3,4-tetrahydronaphthyl)]-4-diethylaminobutanehydroacetate;

1-(3-Iodophenyl)-1-[2-(1,2,3,4-tetrahydronaphthyl)]-4-aminobutanehydrobromide;

1-(3-Methylphenyl)-1-[2-(1,2,3,4-tetrahydronaphthyl)]-4-piperadinobutanemethiodide;

1-(4-Trifluoromethylphenyl)-1-[1-(1,2,3,4-tetrahydronaphthyl)]-4-allylmethylamino-1-butene;

1-Phenyl-1-[2-(1,2,3,4-tetrahydronaphthyl)]-4-di-isopropylaminobutanehydroiodide;

1-(4-Iodophenyl)-1-[1-(1,2,3,4-tetrahydronaphthyl)]-4-di-n-butylamino-1-butene;

1-(2-Methylphenyl)-1-[2-(1,2,3,4-tetrahydronaphthyl)]-4-di-allylamino-1-butenehydrochloride;

1-(4-Methoxyphenyl)-1-[2-(1,2,3,4-tetrahydronaphthyl)]-4-ethylaminobutane;

1-(3-Methoxyphenyl)-1-[2-(1,2,3,4-tetrahydronaphthyl)]-4-diethylaminobutanehydrochloride;

1-(2-Methoxyphenyl)-1-[2-(1,2,3,4-tetrahydronaphthyl)]-4-morpholinobutane;

[4-Phenyl-4-[2-(1,2,3,4-tetrahydronaphthyl)]butyl]-trimethylammoniummethanesulfate

In accordance with the invention, the butenyl compounds are prepared byreacting an amine with a suitably substituted butene bearing a readilydisplaceable group. More specifically, a1-aryl-1-benzocycloalkyl-1-butene, with a displaceable group in the4-position, is treated with an amine, thereby providing the aminobutenesof this invention. Some examples of amines useful in preparing compoundsdisclosed herein include ammonia, methylamine, ethylamine,isopropylamine, n-butylamine, allylamine, 4-hexenylamine, dimethylamine,diethylamine, diisopropylamine, diallylamine, methylethylamine,methylallylamine, ethyl(2-methyl-3-butenyl)amine, trimethylamine,triethylamine, tri-n-propylamine, triallylamine, tri-3-hexenylamine,piperadine, pyrrolidine, morpholine, and the like. Preferred butenestarting materials are those wherein the displaceable group is a halogenatom, especially chlorine, bromine, or iodide. Typical butenes useful inpreparing the compounds of the invention include1-phenyl-1-(2-indanyl)-4-chloro-1-butene,1-(3-methoxyphenyl)-1-(1-indanyl)-4-bromo-1-butene,1-(4-chlorophenyl)-1-[1-(1,2,3,4-tetrahydronaphthyl)]-4-iodo-1-butene,1-phenyl-1-[2-(1,2,3,4-tetrahydronaphthyl)]-4-chloro-1-butene, and thelike. The amine and the suitably substituted butene are normallycommingled in approximately equimolar quantities, although an excess ofeither reactant can be employed if desired. The reaction is best carriedout in an unreactive organic solvent. A suitably solvent can be selectedfrom among any of a number of unreactive organic solvents, includingalcohols such as methanol, ethanol, isopropanol; chlorinatedhydrocarbons such as chloroform or dichloromethane; aromatic solventssuch as benzene, toluene, or xylene; ethers such as diethyl ether,1,2-dimethoxyethane or dioxane, and the like. Mixtures of solvents canbe used if desired, for example a mixture of ethanol and benzene orethanol and water. A preferred reaction solvent is ethyl alcohol, oralternatively a mixture of ethyl alcohol and benzene. The reaction issubstantially complete after about 10 to 20 hours when carried out at atemperature below about 150° C. Generally, the temperature is maintainedin the range of about 50° to 100° C. The product is a primary,secondary, or tertiary amine, or a quaternary ammonium salt, dependingupon the particular aminating agent used in the reaction. When theaminating agent is a tertiary amine for example, the product is thecorresponding quaternary ammonium salt. Generally, the quaternaryammonium salts are highly crystalline solids and can be filtered fromthe reaction mixture and further purified if desired, for example byrecrystallization. When the product is a primary, secondary or tertiaryamine, such product can be isolated either as the free amine or as anacid addition salt by suitable adjustment of the pH. For example, thereaction mixture can be evaporated to dryness and the residueredissolved in water. The pH of the aqueous solution can be adjusted toabout 8 to 10 by the addition of a suitable base, such as aqueous sodiumhydroxide for example. The basic solution is then extracted with asuitable water immiscible organic solvent, such as ethyl acetate ordiethyl ether for instance, and the organic solution can then beevaporated to give the product in the form of the free amine. The freeamine can be further purified if desired by standard methods such asdistillation, chromatography, crystallization, or the like.Alternatively, the free amine can be isolated as an acid addition saltby treating the amine with a suitable acid, especially a mineral acidsuch as hydrochloric or hydrobromic acid for example, in a mutualsolvent such as ethyl acetate or diethyl ether, thereby precipitatingthe corresponding acid addition salt. Generally, the amine acid additionsalts are highly crystalline solids and can be filtered and furtherpurified if desired by recrystallization from solvents such as ethanol,ethyl acetate, water, or the like. When desired, the acid addition saltscan be converted back to the free amine by basification, for example bythe addition of an appropriate base such as sodium hydroxide or sodiumbicarbonate.

The preferred aminobutenes of the invention are those wherein the amineis a tertiary amine, such as a dialkylaminobutene for instance. Thesetertiary amines can be converted to quaternary ammonium salts by normalprocedures that are discussed in detail hereinbelow. Additionally, theprimary and secondary aminobutenes can be converted to secondary,tertiary and quaternary compounds by general alkylation procedures thatare discussed hereinbelow. The aminobutenes of this invention exist ascis and trans isomers, as well as mixtures thereof. It will beunderstood that the separated isomers, as well as the mixtures ofgeometrical isomers, are included within the scope of this invention.

In a further embodiment of the invention, the aminobutenes prepared asdescribed hereinabove are reduced to provide the aminobutanes of theinvention. More specifically, the aminobutenes can be reduced byhydrogenation wherein the aminobutene is dissolved in an inert solventand hydrogenated with hydrogen in the presence of a suitablehydrogenation catalyst. Suitable inert solvents include alcohols such asmethanol or ethanol; esters such as methyl acetate or ethyl acetate; orethers such as diethyl ether or tetrahydrofuran. The particular solventselected for the reaction is not critical, but preferably the solventused is one in which the aminobutene is at least partially soluble.Suitable hydrogenation catalysts include certain noble metals such asplatinum, palladium, or rhodium, as well as active grades of Raneynickel. The noble metal catalysts may be employed as finely dividedmetals, such as that obtained by the hydrogenation of platinum oxide inthe hydrogenation apparatus for example. Alternatively, the metalcatalysts can be employed as deposited on the surface of an inertsupport such as carbon, alumina, barium sulfate, calcium carbonate, orthe like. A preferred hydrogenation catalyst, for example, is palladiumon carbon. The reduction reaction is generally carried out at atemperature below about 100° C., preferably at a temperature in therange of about 0° to 50° C. The hydrogen gas pressure is normallymaintained in the range of about 30 to 2000 p.s.i., preferably at about50 to 100 p.s.i., and the reaction is substantially complete after about2 to 20 hours. The aminobutanes thus prepared can be recovered byremoval of the hydrogenation catalyst, for example by filtration, andevaporation of the solvent to provide the free amine. Furtherpurification can be accomplished, if desired, by normal procedures suchas distillation or chromatography. The acid addition salts are readilyobtained by reaction of the aminobutane with the appropriate acid, asdescribed hereinabove for the aminobutenes.

An alternative method of preparation of the aminobutanes of theinvention comprises catalytic reduction of1-aryl-1-benzocycloalkyl-4-halo-1-butenes to provide the correspondinghalobutanes, which can then be aminated with an appropriate amine toprovide the desired 1-aryl-1-benzocycloalkyl-4-aminobutanes.

It is to be understood that reduction of a butene provides a butanewhich possess an asymmetric center and thus exists as d and lstereoisomers. Both the d and the l isomer, as well as the dl mixture,are included within the scope of the present invention.

As hereinbefore indicated, the aminobutenes and aminobutanes, whereinthe amino group is primary, secondary, or tertiary, can be converted topharmaceutically acceptable acid addition salts by the reaction of theappropriate acid with the free amine in a mutual solvent. Similarly,these aminobutenes and aminobutanes can be converted to quaternaryammonium salts which are valuable pharmacological agents. Generally, atertiary amine, for example a1-aryl-1-benzocycloalkyl-4-dialkylaminobutane, is treated with analkylating agent in an unreactive solvent to provide the correspondingquaternary ammonium salt. Typical unreactive solvents include acetone,benzene, diethyl ether, methanol, tetrahydrofuran, or the like. Typicalalkylating agents used to quaternize the amine are lower alkyl halidessuch as methyl chloride, ethyl iodide, allyl bromide, as well as alkylsulfates such as methyl sulfate or ethyl sulfate. The reactants arenormally employed in approximately equimolar amounts; however, an excessof either can be used if desired. The product quaternary salts aretypically crystalline solids and are generally recovered by filtration.When the quaternary salt has a halogen anion, such as chloride or iodidefor example, these anions can be converted to other anions when desired,as indicated hereinabove. More specifically, a quaternary ammoniumhalide can be reacted with aqueous silver oxide to afford silver halideand the corresponding quaternary ammonium hydroxide. The quaternaryammonium hydroxide can then be neutralized with an appropriate acid,such as methanesulfonic acid, acetic acid, butyric acid, nitric acid,p-toluene-sulfonic acid, or the like, thereby providing thecorresponding pharmaceutically acceptable quaternary ammonium salt.

Alkylation of aminobutenes and aminobutanes, wherein the amino group isprimary or secondary, can be carried out when desired. For example, aprimary aminobutane can be further alkylated with an appropriatealkylating agent to provide the corresponding secondary aminobutane,which can be alkylated still further to provide the correspondingtertiary amine. The alkylation reactions are general and are well knownto those in the art.

As hereinbefore indicated, the preferred starting materials for thecompounds of this invention are 1-aryl-1-benzocycloalkyl-4-halobutenes.These compounds are readily available from known starting materials.More specifically, the disubstituted halobutenes are generally preparedfrom benzocycloalkyl aryl ketones, which compounds are well known. Inparticular, a benzocycloalkyl aryl ketone, such as 2-indanyl phenylketone for example, is treated with a cyclopropyl Grignard reagent toprovide a benzocycloalkyl aryl cyclopropyl carbinol. The cyclopropylcarbinol is treated with an acid, especially a mineral acid such ashydrochloric or hydroiodic acid for example, thereby opening thecyclopropyl ring and dehydrating the alcohol to afford the correspondingdisubstituted butenyl halide.

The reaction of a benzocycloalkyl aryl ketone with a cyclopropylGrignard reagent is preferably carried out in an unreactive organicsolvent. Solvents generally used for Grignard reactions are well knownto those in the art and include solvents such as diethyl ether, diglyme,1,2-dimethoxyethane, dioxane, furan, tetrahydrofuran, and the like. Theparticular solvent selected is not of a critical nature. The Grignardreagent is prepared by established procedures which comprise reactingmagnesium metal with the appropriate alkyl halide, in particular acyclopropyl halide such as cyclopropyl bromide for example. Thecyclopropyl magnesium halide is then reacted with the benzocycloalkylaryl ketone, normally in an equimolar amount; however, either can beused in excess of the other if desired. Preferably, the Grignard reagentis employed in slight excess of the ketone in order to ensure morecomplete reaction. The reaction is generally carried out at atemperature below about 150°, the most convenient temperature being thereflux temperature of the particular solvent being used. The reaction issubstantially complete within about 2 to 12 hours, although longerreaction times are generally not detrimental to the production of theproduct. The product, a cyclopropyl benzocycloalkyl aryl carbinol, isrecovered by hydrolyzing the reaction mixture with a proton source, suchas water for example, and extraction of the product into a suitablesolvent, such as diethyl ether or ethyl acetate. Evaporation of thesolvent affords the desired carbinol which can be used directly, or ifdesired, the carbinol can be further purified by standard procedures,such as distillation or chromatography for example.

The cyclopropyl benzocycloalkyl aryl carbinol is treated with a suitableacid to effect ring opening of the cyclopropyl ring system andconcomitant dehydration. Preferred acids for the reaction include themineral acids such as hydrochloric, hydrobromic, or hydroiodic acid.Acids such as methanesulfonic or p-toluenesulfonic acid can be used ifdesired. The reaction is generally carried out in an essentiallyanhydrous organic solvent; however, the particular solvent is notcritical. Typical solvents generally employed include lower alkanoicacids such as formic acid, acetic acid or propionic acid; ethers such asdioxane; or amides such as N,N-dimethylformamide can also be used. Thereaction is carried out at a temperature below about 70° C, preferablyat a temperature in the range of about 0° to 30° C. The reaction isnormally complete within about 1 hour to about 8 hours. The product, abenzocycloalkyl aryl butene, can be recovered by diluting the reactionmixture with a suitable solvent, preferably water, and extracting thebutene into a water immiscible solvent such as diethyl ether or ethylacetate. If desired, the butene can be further purified by normalprocedures such as distillation, crystallization or chromatography.

The compounds of this invention are useful pharmacological agents,especially in the treatment of cardiac arrhythmias in humans. Thecompounds can be administered by the oral route or by the parenteralroute, and in cases of severe arrhythmias, it may be desirable toadminister the compounds intraveneously. Generally, a compound of thisinvention can be employed in combination with one or morepharmaceutically acceptable diluents or carriers. For oraladministration, for example, the compound of this invention can be mixedwith carriers such as starch powder, sucrose, cellulose, magnesiumstearate, and the like. The dose can be formulated as a tablet or as acapsule. The normal adult oral dose will contain from about 0.005 toabout 2.0 g. of active ingredient, and will be administered to a patientsuffering from an arrhythmia at intervals of about 4 to 10 hours until atolerance level has been reached, or until a conversion to a normalrhythm is maintained. The pharmaceutical preparations may contain, inaddition to the active component of the present invention, one or moreother pharmacologically active substances, especially otherantiarrhythmic agents such as lidocaine for example.

In the case of parenteral administration, the intravenous route ispreferred. A suitable pharmaceutical preparation for intravenousadministration will include a compound of this invention in the amountof from about 0.1 to about 1.0 g. admixed with a suitable carrier suchas 5 percent aqueous glucose or 0.9 percent saline solution for example,generally in the amount of about 50 to 100 cc. of solution. Such asolution can be administered dropwise to a patient suffering from anarrhythmia over a period of from 5 to about 60 minutes. The compounds ofthis invention are especially useful in patients refractory to otherantiarrhythmic agents such as procainamide or quinidine for example.

The following detailed examples are added to more fully illustrate, butnot to limit, the scope of the invention.

EXAMPLE 1 1-Phenyl-1-(2-indanyl)-4-diethylamino-1-butene

To a solution of 29.5 g. of 1-phenyl-1-(2-indanyl)-4-chloro-1-butene in125 cc. of 95 percent (v/v) ethanolbenzene (commercial 2B ethanol) wasadded 100 cc. of diethylamine in one portion. The reaction mixture wasshaken and heated in a sealed bomb to about 100° C for 16 hours. Thereaction mixture was cooled to about 25° C. and the solvent was removedunder reduced pressure to afford the product as an oily residue. The oilwas dissolved in 400 cc. of diethyl ether and shaken with 5N sodiumhydroxide and washed with water. The ethereal solution was dried and thesolvent was removed under reduced pressure, affording1-phenyl-1-(2-indanyl)-4-diethylamino-1-butene.

EXAMPLES 2-5

The following aminobutenes are prepared by the procedure of example 1,from the corresponding halobutene and amine.

1-Phenyl-1-(1-indanyl)-4-methylamino-1-butene;

1-(4-Chlorophenyl)-1-(2-indanyl)-4-amino-1-butene;

1-(4-Methylphenyl)-1-(2-indanyl)-4-allylmethalamino-1-butene;

1-Phenyl-1-[2-(1,2,3,4-tetrahydronaphthyl)]-4-ethylisopropylamino-1-butene.

EXAMPLE 6 1-Phenyl-1-(2-indanyl)-4-diethylamino-1-butene hydrogenoxalate

A solution of 693 mg. of oxalic acid in 20 cc. of ethyl acetate wasadded to a solution of 1-phenyl-1-(2-indanyl)-4-diethyl aminobutene in30 cc. of ethyl acetate. The reaction mixture was allowed to stand atroom temperature for 2 hours, at which time the crystalline product wasfiltered to provide the oxalate salt of1-phenyl-1-(2-indanyl)-4-diethylamino-1-butene. M.P. 98°-101° C.

EXAMPLE 7 1-Phenyl-1-(2-indanyl)-4-diethylamino-1-butene hydrochloride

Dry hydrogen chloride gas was bubbled into a solution of1-phenyl-1-(2-indanyl)-4-diethylamino-1-butene in diethyl ether. Theethereal solution was concentrated under reduced pressure to provide theproduct as a white solid residue which was purified by recrystallizationfrom an ethyl acetateligroin solvent mixture. Crystalline1-phenyl-1-(2-indanyl)-4-diethylamino-1-butene hydrochloride wasrecovered by filtration. M.P. 110°-112° C.

Analysis, Calc. for C₂₃ H₃₀ NCl (percent): C, 77.61; H, 8.50; N, 3.99;Cl, 9.96.

Found (percent): C, 77.41; H, 8.61; N, 3.76; Cl, 10.17.

EXAMPLE 8 1-Phenyl-1-(2-indanyl)-4-diethylaminobutane

A solution of 23.5 g. of 1-phenyl-1-(2-indanyl)-4-diethylamino-1-butenein 375 cc. of 95 percent (v/v) ethanolbenzene was stirred while 1.5 g.of 5 percent palladium on carbon was added in one portion. The reactionmixture was stirred for 6 hours at 24° C. under a hydrogen gasatmosphere at 60 p.s.i. After filtering off the hydrogenation catalyst,the filtrate was concentrated to dryness under reduced pressure toprovide 1-phenyl-1-(2-indanyl)-4-diethylaminobutane.

EXAMPLES 9-11

The following aminobutanes are prepared by the method of Example 8 fromthe corresponding aminobutenes:

1-Phenyl-1-(2-indanyl)-4-aminobutane;

1-Phenyl-1-(2-indanyl)-4-ethylaminobutane;

1-(4-Chlorophenyl)-1-[1-(1,2,3,4-tetrahydronaphthyl)]-4-diethylaminobutane.

EXAMPLE 12 1-Phenyl-1-(2-indanyl)-4-diethylaminobutane hydrochloride

To a solution of 1-phenyl-1-(2-indanyl)-4-diethylaminobutane in diethylether was added anhydrous hydrogen chloride gas. The reaction mixturestood at room temperature for 20 minutes, and the solvent was thenremoved under reduced pressure, leaving the product as a solid residue.The product was recrystallized from ethyl acetate, affording1-phenyl-1-(2-indanyl)-4-diethylaminobutane hydrochloride. M.P. 132°-34°C.

Analysis, Calc. for C₂₃ H₃₂ NCl (percent): C, 77.17; H, 9.01; N, 3.91;Cl, 9.90.

Found (percent): C, 77.09; H, 8.98; N, 3.81; Cl, 9.99.

EXAMPLE 13 4-Phenyl-4-(2-indanyl)-butyldiethylmethylammoniummethanesulfate

To a stirred solution of 3.14 g. of1-phenyl-1-(2-indanyl)-4-diethylaminobutane in 50 cc. of benzene wasadded 1.26 g. of dimethyl sulfate. The reaction mixture was stirred atroom temperature for 12 hours. The crystalline product was filtered offand recrystallized from ethyl acetate and methanol, providing 3.85 g. of4-phenyl-4-(2-indanyl)-butyldiethylmethylammonium methanesulfate. M.P.118°-121° C.

Analysis, Calc. for C₂₅ H₃₇ NO₄ S (percent): C, 67.08; H, 8.33; N, 3.13;S, 7.16.

Found (percent): C, 67.37; H, 8.11; N, 3.17; S, 7.01.

EXAMPLE 14 1-Phenyl-1-(2-indanyl)-4-methyl-n-propylaminobutane

A solution of 1-phenyl-1-(2-indanyl)-4-bromobutane in ethanol wasstirred at room temperature while methylpropylamine was added. Thereaction mixture was stirred several hours at about 100° C. Aftercooling the reaction mixture to room temperature, the solvent wasremoved under reduced pressure, affording1-phenyl-1-(2-indanyl)-4-methyl-n-propyl-aminobutane.

I claim:
 1. A method of treating cardiac arrhythmias comprisingadministering to a human subject suffering from an arrhythmia and inneed of treatment a compound of the formula ##STR3## wherein: m is 0, 1,or 2; n is 0, 1, or 2; m + n is 2 or 3;R₁ and R₂ independently arehydrogen, C₁ -C₄ alkyl, lower alkenyl of the formula CH₂ R₄, wherein R₄is C₂ -C₅ alkenyl, R₃ is hydrogen, methyl, methoxy, trifluoromethyl, orhalogen; X and Y are both hydrogen, or taken together form a doublebond; or the pharmaceutically acceptable acid addition salts thereof; inthe amount of about 0.005 to about 2.0 g. at intervals of about 4 toabout 10 hours, either orally or parenterally.
 2. The method accordingto claim 1 wherein in the compound being administered, R₁ and R₂independently are C₁ -C₄ alkyl.
 3. The method according to claim 2wherein in the compound being administered, m is 1 and n is
 1. 4. Themethod according to claim 3 wherein the compound administered is4-phenyl-4-(2-indanyl)-1-diethylaminobutane.